Neoantigen TCR T-cell Therapy Shows Early Proof-of-Concept in Solid Tumors

Stefanie J. Mandl, PhD

A personalized neoantigen-specific and off-the-shelf T cell receptor (TCR) T-cell therapy utilized through CRISPR gene editing technology demonstrated feasibility and tolerability in 16 patients across multiple tumor types, according to first-in-human phase 1a findings presented during the 2022 SITC Annual Meeting.¹ 

“Our clinical study offers early proof of concept for several steps that are required for achieving the goal of truly personalized TCR T-cell therapies, and those include the isolating and cloning of multiple TCRs that recognize patient-specific mutational neoantigens, [and] utilizing single-step, non-viral precision gene editing to simultaneously knock-out the endogenous TCRs and knock-in the patient-specific neo[antigen-targeted] TCRs,” Stefanie J. Mandl, PhD, chief scientific officer of PACT Pharma, said in a presentation during the meeting.

The results of the phase 1a trial (NCT03970382), which were also published in Nature², also demonstrate the clinical-grade manufacturing of neoantigen-targeted TCR (neoTCR)-engineered T-cell products with defined composition of up-to-3 TCRs per patient.

“We really hope that our study paves the way for the continued advancement of TCR T-cell therapies that are personalized,” Mandl said, noting that the final cell product demonstrated an improved GMP manufacturing process, which had gone through 4 versions.

Eighty-eight patients met eligibility criteria and had sufficiently good tissue biopsies and human peripheral blood mononuclear cells for the analysis. Of these, more than 50,000 neoantigens were predicted in a library of 64 human leukocyte antigens (HLAs). Additionally, up to 352 neoantigen-HLA reagents were produced per patient, totally approximately 12,000 neoantigen-HLAs that successfully expressed. From this, investigators identified over 900 neoTCRs.

The personalized adoptive cell therapy highlighted at the meeting begins and ends with patients’ own cells and occurs in 2 phases: a clinical-grade screening phase where TCRs are discovered, validated, and selected, and an enrollment phase in which patients undergo leukapheresis and their autologous product is manufactured.

For this trial, 3 platforms were created: an isolation and cloning of neoepitope TCRs for each patient, a completely viral CRISP genome-editing platform to knock out endogenous TCRs and insert new TCRs, and a manufacturing process of an up-to-3 neoTCR product. Once infused back into the patient, the engineered T cells were redirected into their immune system to recognize the cancer.

Across 9 clinical sites, patients spanning multiple solid tumor types were enrolled, including melanoma, non–small cell lung cancer (NSCLC), urothelial cancer, colorectal cancer (CRC), head and neck cancer, ovarian cancer, breast cancer, and prostate cancer.

Following the neoTCR discovery and product selection and patient enrollment/leukapheresis phases, bridging therapy was permitted per principal investigation discretion. They then underwent conditioning chemotherapy with fludarabine at 30 mg/m² for 4 days plus cyclophosphamide at 600 mg/m² for 3 days on days -6 to -3 prior to neoTCR-P1 cell infusion. Pre- and post-infusion biopsies were obtained in all patients if possible and serial biomarker assessments were conducted.

First tumor assessments occurred at day 28, and imaging occurred at day 56 and every 2 months for the first year, and every 3 months for the second year.

The phase 1a trial encompassed 3+3 dose-escalation and dose-expansion phases. In the dose-escalation portion, patients were enrolled at a starting dose of 4 x 10⁸ neoTCR-P1 cells before being escalated to 1.3 x 10⁹ neoTCR-P1 cells and then 4 x 10⁹ neoTCR P1 cells.

The dose-expansion phase utilized neoTCR-P1 alone or in combination with interleukin-2 (IL-2) at 500,000 IU/m² subcutaneous twice daily for up to 14 doses.

The coprimary end point is the feasibility of TCR discovery and manufacturing of a multi-TCR product using complete non-viral gene editing, and incidence and nature of dose-limiting toxicities. Secondary outcome measures are objective response rate, duration of response, progression-free survival, and overall survival.

Twenty-eight patients underwent leukapheresis, and 16 patients were dosed with NeoTCR-P1 either alone (n = 12) or with IL-2 (n = 4). All 16 patients were evaluable. The median age was 47 years (range, 35-69) and 10 patients were male. Most had microsatellite stable CRC (n = 11), followed by hormone receptor–positive breast cancer (n = 2), ovarian cancer (n = 1), melanoma (n = 1), and NSCLC (n = 1). The median number of prior regimens was 5 (range, 2-9).

Four patients had 1 TCR, 3 had 2, and 9 patients had 3 TCRs. Following treatment, 5 patients had stable disease and the remaining 11 had progressive disease.

Regarding safety, the grade 3 or higher adverse effects (AEs) included anemia (n = 2), febrile neutropenia (n = 1), pancytopenia (n = 2), thrombocytopenia (n = 1), lymphopenia (n = 2), neutropenia (n = 7), leukopenia (n = 4), Herpes Zoster infection (n = 1), and encephalopathy (n = 1). Mandl noted that most AEs were linked to the conditioning chemotherapy. However, the encephalopathy and grade 1 cytokine release syndrome were related to NeoTCR-P1 treatment.

Mandl also explained that the treatment demonstrates the ability of the infused transgenic T-cell products to traffic to patient tumors, and that a retrospective analysis directs the design of future programs for increased efficacy and durability.

Antoni Ribas, MD, PhD, professor of medicine and surgery at the University of California, Los Angeles, and a corresponding author of the Nature paper, commented on the data in a news release.³

“This study represents a significant leap forward in efforts to develop a personalized treatment for cancer that utilizes isolated immune receptors that can specifically recognize mutations within a patient’s own cancer,” Ribas, a 2015 Giant of Cancer Winner in the melanoma category, said. “The work highlighted at SITC and within the Nature paper paves the way for the continued advancement of research aimed at delivering safe and effective, patient specific TCR T-cell therapies for the treatment of cancer.”

References

1. Foy SP, Jacoby K, Bota DA, et al. A phase I study of personalized adoptive TCR T cell therapy in patients with solid tumors: safety, efficacy, and T cell trafficking to tumors of non-virally gene edited T cells. Presented at: 2022 SITC Annual Meeting; November 8-12; 2022; Boston, MA. Abstract 1478.
2. Foy SP, Jacoby K, Bota DA, et al. Non-viral T cell receptor replacement for personalized cell therapy. Nature. Published online November 10, 2022. doi:10.1038/s41586-022-05531-1
3. PACT Pharma reports data from first clinical study using CRISPR to substitute a gene in patients’ immune cells to treat cancer. News release. Pact Pharma. November 10, 2022. Accessed November 10, 2022. https://prn.to/3A1FGq0